This preliminary investigation is designed to identify CNS regions involved in the response to ipsapirone challenge (a 5-HT1A receptor agonist) in normal controls and depressed patients. It extends our current efforts to identify CNS regions responding to monoaminergic challenges in these groups. Numerous studies on the biochemistry, electrophysiology, and behavioral pharmacology of 5-HT1A receptor ligands have indicated that 5-HT1A receptors play a major role in modulating serotonergic neurotransmission and that serotonin plays a key role in core behaviors of mood disorders. Patients symptomatic with RDC Endogenous and DSM IV Melancholic Major Depressive Disorder (ED) (n=24) will be compared to age/gender matched normal controls (n=24)to 1) identify and characterize changes in the 3- dimensional (3-D) distribution of regional cerebral blood flow (rCBF) induced by ipsapirone (IPS) challenge vs. placebo as measured by dual- isotope 3-headed high resolution full-volume Single Photon Emission Computerized Tomography (SPECT); and 2) determine if IPS-induced rCBF changes distinguish between normals and depressed patients. We will study patients with RDC definite endogenous and DSM IV Melancholic type major depression to reduce heterogeneity within the depressed group and because resting studies using SPECT indicate that ED and non-ED differ in patterns of CNS functional abnormalities. Patients will be diagnosed by SCID and RDC criteria and have a 17-item Hamilton Rating for Depression Score greater than or equal to 18. All subjects will be drug-free for at least 2 weeks. In a fixed-order, single-blind design subjects will receive placebo than IPS (0.3 mg/kg p.o.). This dose is similar to previous IPS challenge human studies. The experimental plan provides two major opportunities: 1) to test hypotheses based on existing animal data on the serotonergic systems regarding the location and nature of IPS-induced rCBF changes (such hypotheses address a delineation of the functional neuroanatomy of the 5-HT1A system); and 2) to provide original data for hypothesis generation as to whether, and how, 5-HT1A receptor-associated systems differ functionally and/or regionally between the groups under study. Results will determine whether the functional status of CNS 5-HT1A receptor- associated systems differentiate symptomatic depressed from normals.